Cranial delivery of pharmaceuticals

ABSTRACT

A method for rapid delivery of an active compound to innervate a cranial nerve of a subject. Also provided is a method for treating a disease or condition by topically applying a pharmaceutical composition to the face excluding the palpebral part of the eye, in an amount effective for treating the disease or condition.

BACKGROUND

The most common routes for administering pharmaceuticals are oral,intramuscular, subcutaneous, intravenous, and transdermal. Each routehas its own particular drawback. For example, a drug administered orallyis subjected to harsh conditions including exposure to stomach acids anddigestive enzymes even before it gets into the bloodstream via theintestinal tract, hepatic portal system, and liver. The digestive systemand first pass metabolism can greatly diminish the activity of thepharmaceutical. As a result, larger doses of the drug are required,leading to undesirable side effects. Despite large drug doses, in manyinstances the drug may still not reach target tissues such as the brain,head, and neck. The area inside the eye and behind the eye are examplesof body areas to which it is difficult to deliver a drug effectively.

Typically, ophthalmic drugs in the form of an eye drop or an ointmentare applied to the front of the eye, which is designed to protect theeyes from foreign substances. Drugs administered in this manner do notreach inside or behind the eye. More importantly, other typical drugdelivery routes do not allow the drug to induce the desired therapeuticeffect at the target gland or tissue.

Injectable drugs enter the circulation immediately but can haveundesirable systemic effects.

Transdermal methods of delivery allow the absorption of medicinedirectly through the skin. Gels, emulsions, creams, sprays and patchesare easy to use and are effective for transdermal delivery of a drug.However current transdermal delivery routes are utilized for deliveringa drug either to exert a local effect or to enter the blood circulation.

Pharmaceuticals administered by all of the routes described above enterthe bloodstream. Additionally, drugs in the circulation cannot alwaysreach all areas of the body. For example, many drugs cannot pass throughthe blood-brain barrier. It also can be difficult to deliver a drug toan area of the body that is not well vascularized.

The need exists for new routes of drug administration that allow forlower doses to be administered and that allow access of the drug toareas of the body which are difficult to treat, such as the brain, eyes,and other head and neck regions.

SUMMARY

One aspect of this invention relates to a method for delivery of a drugwhich rapidly acts on a cranial nerve of a subject. The method includesthe steps of obtaining a topical composition that includes the drug anda pharmaceutically acceptable excipient, and applying the topicalcomposition to an area of the face of the subject not including thepalpebral part of the eye.

In one embodiment, a method is provided for treating oropharyngealdysphagia by administering a cannabinoid to the subject. The cannabinoidis administered topically to the subject on an area of the face notincluding the palpebral part of the eye.

Also provided is a method for treating a subject having a diseasemediated by a neurotropic microbe, e.g., a virus, a bacteria, a fungus,or a mold. In this method, an antimicrobial agent, e.g., an antiviral,an antibacterial, or an antifungal, is topically administered to thesubject on an area of the face not including the palpebral part of theeye.

In a further aspect, a method for treating an ophthalmic disease orcondition is disclosed. The method is carried out by topicallyadministering an effective amount of a pharmaceutical composition to asubject in need thereof by applying it to an area of the face notincluding the palpebral part of the eye. The ophthalmic disease orcondition that can be treated is glaucoma, allergic conjunctivitis,ocular rosacea, retinal vasculitis, bullous pemphigoid, mucous membranepemphigoid, Sjogren's syndrome, episcleritis, scleritis, uveitis, opticneuritis, ischemic optic neuropathy, pain, dry eye, maculardegeneration, diabetic retinopathy, herpes simplex keratitis, orendophthalmitis.

Also provided is a topical pharmaceutical composition for treatingoropharyngeal dysphagia. The composition includes a cannabinoid andpharmaceutically acceptable excipients, wherein the composition providesa dose of cannabinoid from 0.1 mg to 20 mg.

The details of one or more embodiments are set forth in the descriptionand the examples below. Other features, objects, and advantages will beapparent from the detailed description of several embodiments and alsofrom the claims.

DETAILED DESCRIPTION

An innovative cranial drug delivery route is disclosed in which topical,nasal, intradermal, or subcutaneous drug delivery innervate cranialnerves, e.g., the trigeminal and the facial nerves, providing a novelmodality for treatment and potential cure of diseases and conditionsthat cannot be treated easily via the vascular system. The topicalcomposition can contain the active drug in concentrations from about0.01% by weight to about 80% by weight. Any of the pharmaceuticalsdescribed below can be formulated with appropriate excipients known inthe art. The formulation can be, e.g., a liquid or semi-solid, asolution, a suspension, an emulsion, a gel, a cream, a lotion, anointment, or a patch. Delivery can be simple or actively assisted by anelectric current or other electrophysical device. The pharmaceutical canbe administered by applying it to the forehead. In an alternativeembodiment, the pharmaceutical can be administered by iontophoresis orby subcutaneous or intradermal injection to the forehead.

The composition of the present invention can be applied topically to theface to the regions that are outside of the palpebral part of the eye.The palpebral part of the eye refers to the region of and around the eyeassociated with the palpebral component of the orbicularis oculi musclegroup. The palpebral component of the muscles originates in thepalpebral ligament and runs above and below the eye to the lateral angleof the eye, forming concentric circles around the eye. The palpebralpart of the eye thus refers to the facial surface around the eye thatcorresponds to the location of the palpebral component of theorbicularis oculi muscle lying underneath the facial skin. Non-limitingexamples of these regions include, for example, the forehead above theeyebrows, the temple area between the end of the eyebrow and thehairline including the temple region, the upper cheek, or the sides orbridge of the nose. In one embodiment, the composition of the presentinvention is applied to the forehead. In another embodiment, thecomposition is applied to one or both temple regions. In a furtherembodiment, the composition is applied to the upper cheek. In anotherembodiment, the composition is applied to one or both sides or thebridge of the nose. In one embodiment, the composition is applied to twoor more regions of the face simultaneously or sequentially, andproximately or distant in time. For example, the composition can beapplied to the forehead, and further applied to the temple region at thesame time or at the next prescribed time, whether such next prescribedtime is the same day or a different day. In one embodiment, thecomposition is applied to the same region of the face each time it isapplied. In another embodiment, the composition is applied to any areaof the skull, exclusive of the palpebral part of the eye. In a furtherembodiment, the composition can be applied intranasally to the mucousmembrane inside of the nose.

Not to be bound by theory, it is believed that topical application of apharmaceutical or other compound to the forehead and temple areasresults in rapid delivery and/or action, i.e., within less than 10minutes, via a cranial nerve, including cranial nerve V (trigeminalnerve), VII (facial nerve), I, II, III, IV, VI, VIII, IX, X, XI, andXII, or rapid entry into the microcirculation of the vascular system. Itis also believed that the rapid action of drugs delivered cranially canbe attributed to drug absorption of the drug through the skin of theforehead, uptake by receptors residing in nerve endings in the skin andinduction of signaling in the brain. The brain can then respond to thedrug by sending appropriate signals to target muscles, glands, andorgans. A drug delivered to a cranial nerve can exert its effect on anorgan or gland that is innervated by that nerve. Another advantage ofthis drug delivery route is evidenced by the observation that nervesdamaged, extirpated, or infected by a virus, e.g., a neurotropic virus,can be treated by the method described above. Additionally, a much lowerdose of active drug, as compared to the dose required for systemicdelivery, can be effective, thereby enhancing safety.

The cranial drug delivery method can be used advantageously to treatdiseases and conditions including but not limited to CNS diseases suchas traumatic brain injury and neurodegenerative diseases, pain,especially neuropathic pain that cannot be treated effectively withcurrent pain drugs, eye diseases and conditions, and infections due toneurotrophic microbes. Microbe as used here refers to a virus, abacteria, a fungus, or a mold. The method is particularly effective whenpracticed on a mammal, including but not limited to dogs and humans.

Among the advantages of the disclosed cranial drug delivery method ascompared to typical methods is that a lower dose of drug is required toproduce a therapeutic effect, thereby minimizing side effects. It hasalso been found that a dose of a drug ineffective when administeredsystemically is effective if applied cranially. The delivery route isconvenient, allowing administration to people who cannot take oraldrugs. It is also less cumbersome than injectables and can be accuratelydosed. Drugs administered by cranial delivery are faster acting,rendering drug half-life less relevant as compared to systemicadministration. The method also renders unnecessary intravitreousinjections which are painful and risky.

The cranial delivery method also allows for greater flexibility inadministering drug combinations. For example, two drugs that aretypically taken at different times of day can be administeredsimultaneously via the cranial delivery method. More specifically, adrug that must be taken on an empty stomach can be co-administered witha drug that must be taken after a meal. Additionally, multi-drugregimens can be simplified by administering all drugs togethercranially. For example, many elderly patients who are prescribedmultiple medications forget to take one or more of the medications asdirected. The cranial delivery method can be used to deliver acombination of the prescribed medications in a single application, thusavoiding accidental non-compliance. Drug mix-ups can also be avoided byproviding a single combination of medication. Cranial delivery can alsoavoid drug irritation issues, e.g., gastric distress, associated withtypical delivery methods.

The cranial delivery method, as mentioned above, has the advantage ofdelivering drugs rapidly and simultaneously. This advantage can beexploited for treating addiction or for tapering drug doses. Forexample, a patient on high dose dexamethasone therapy often cannot bewithdrawn from that medication without suffering serious side effects atlower doses. Tapered doses of dexamethasone can be applied craniallytogether with increasing doses of hydrocortisone to alleviate theeffects of tapering. In another example, an individual addicted to adrug, e.g., an opiate, can be administered diminishing doses ofbuprenorphine cranially until complete withdrawal is accomplished.

Many difficult to treat or previously untreatable conditions canadvantageously be treated by the method described herein.

For example, progesterone or progestins can be administered cranially tocontrol pain, inflammation, and bruising. Progesterone can also bedelivered by the cranial method to treat dry eyes. Progesterone can alsolessen discomfort, redness, and irritation associated with contact lenswear. Cranially administered progesterone can prevent or reduce the riskof cellular damage and the development of dry eye resulting from wearingcontact lenses. The effects of progesterone also allow a contact lenswearer to increase the duration of contact lens wear.

Progesterone can be delivered by the cranial method to stimulate eyelashand eyebrow growth for aesthetic purposes and for treating madarosis,i.e., the loss of eyebrows or eyelashes associated with a medicalcondition or a drug treatment.

Madarosis can be scarring or non-scarring depending upon the etiology.Scarring madarosis is typically treated by follicular unittransplantation. Cranial application of a topical progesteronecomposition can lessen or eliminate the need for such surgicalintervention.

Conditions associated with madarosis include, but are not limited to,atopic dermatitis, seborrhoeic dermatitis, lamellar ichthyosis,psoriasis, frontal fibrosing alopecia, ulerythema ophryogenes, acnerosacea, telogen effluvium, follicular mucinosis, cutaneous sarcoidosis,alopecia areata, discoid lupus erythematosus, en coup de sabre,Graham-Little syndrome, Parry-Romberg syndrome, Vogt Koyanagi Haradasyndrome, leprosy, secondary syphilis, viral infections, fungalinfections, demodicosis, phthiriasis palpebrarum, trichotillomania,tumors, systemic mastocytosis, cutaneous T-cell lymphoma, andtrichodysplasia spinulosa.

Madarosis also results from radiotherapy for ocular tumors, cocaineabuse, drug treatment (e.g., retinoids, heparin, anticonvulsants,angiotensin-converting enzyme inhibitors, androgens, miotics,anticoagulants, anti-cholesterol drugs, antithyroid drugs, propranolol,valproic acid, boric acid, bromocriptine, and chemotherapeutic drugs),hypervitaminosis A, thallium poisoning, and mercury poisoning.

Progesterone, estradiol, and testosterone can be delivered by the methoddescribed above to effect hormone replacement therapy. Hormonereplacement therapy by cranial administration of these hormones canadvantageously be carried out using much lower doses of hormone than istypically prescribed and positive results are achieved in a shortertime. Progesterone or testosterone can be delivered by the method fortreating erectile dysfunction. Progesterone, estradiol, and testosteronecan be delivered by the method described above for management oftransgender conditions. Cranial application of progesterone can improvesurface eye disease, i.e. corneal lesions and thinning as a result ofherpetic keratitis, and can also be used for treating trigeminalneuralgia. Additionally, cranially-delivered progesterone can beeffective for treating symptoms resulting from dyslexia including, butnot limited to, decreased visual acuity, poor reading fluency,difficulty in reading aloud, headlight glare during evening drivingProgesterone delivered cranially can also vastly improve symptoms oftraumatic brain injury. The precursor of progesterone, pregnenolone, orthe metabolites such as allopregnanoline and pregnanolone can also besimilarly applied cranially for treating the above-mentioned diseases orconditions.

The antiviral drug ganciclovir applied cranially can be used fortreating ocular or facial herpes zoster or HSV-1, either active orsubclinical. Cranial shingles and HSV-1 can also be treated withcranially applied ganciclovir, penciclovir, or acyclovir.

Additionally, a cannabinoid, e.g., a delta-9-tetrahydrocannabinol, whichcan be(6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol(“dronabinol”), delivered cranially can be used for treating anorexiainduced by chemotherapy, for treating nausea, and can block theinduction of anorexia by antidepressants. Dronabinol can also be used toelevate blood pressure by applying it to the forehead.

In a particular embodiment, dronabinol can be used to treatoropharyngeal dysphagia. The oropharyngeal dysphagia that can be treatedmay result from the following: (i) iatrogenic causes (e.g., side effectsof medication, chemotherapy, neuroleptics, postsurgical muscular orneurogenic causes, and radiation); (ii) infectious (e.g., diphtheria,botulism, Lyme disease, syphilis, polio, postpolio syndrome, herpes,cytolomegalovirus, and candida); (iii) metabolic (e.g., amyloidosis,Cushing's syndrome, thyrotoxicosis, and Wilson's disease); (iv)myopathic: (e.g., connective tissue disease, (overlap syndrome,dermatomyositis, myasthenia gravis, myotonic dystrophy, oculopharyngealdystrophy, polymyositis, sarcoidosis, and paraneoplastic syndromes); and(v) neurological (e.g., brainstem tumors, head trauma, stroke, cerebralpalsy, Guillain-Barre syndrome, Huntington's disease, multiplesclerosis, tardive dyskinesia, metabolic encephalopathies, amyotrophiclateral sclerosis, Parkinson's disease, and dementia).

Dronabinol delivered cranially to an individual with dementia, e.g.,Alzheimer's disease, can also alleviate anxiety agitation, aggressivebehavior, nocturnal restlessness and disorientation, wandering,disorientation, delusions, depression, and insomnia, among othersymptoms.

As mentioned above, topical compositions for cranial application cancontain the active drug in concentrations from about 0.01% by weight toabout 80% by weight. For example, the concentration of active drug canbe 0.01%, 0.05%, 0.1%, 0.25%, 0.5%, 1%, 2.5%, 5%, 10%, 20%, 25%, 50%,75%, and 80%. The dose of an active drug that can be applied by thismethod can range from 0.01 mg to 100 mg. For example, the dose of activedrug applied can be 0.01 mg 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 80 mg, 90 mg, and100 mg.

In one embodiment, a topical ganciclovir composition can be applied at aconcentration of 0.05-2% by weight of the composition, at a dose of 0.05to 2 mg two to four times a day. For example, 0.15 mg per applicationcan be administered cranially four times daily.

In another embodiment, a 0.1% to 20% by weight formulation ofprogesterone can be applied cranially at a dose of 0.1 to 20 mgprogesterone. For example, 0.25% to 1% progesterone (e.g., 0.25 mg to 1mg) can be applied topically to the forehead as described above. Inanother example, application to the forehead of low dose progesteronegel (0.25% to 1%) effectively increases the length, strength, density,thickness, and curl of eyelashes, and darkens their appearance over apre-treatment baseline.

The topical cranial drug delivery method of this invention can be usedto treat facial palsies caused by infections, including Bell's palsy.Infections can also be treated, including but not limited to externalotitis, otitis media, mastoiditis, chickenpox, diphtheria, Herpes zostercephalicus (Ramsey Hunt syndrome), encephalitis, poliomyelitis (type 1),mumps, mononucleosis, leprosy, influenza, coxsackievirus, malaria,syphilis, tetanus, tuberculosis, botulism, acute hemorrhagicconjunctivitis (enterovirus 70), gnathostomiasis, mucormycosis, Lymedisease, cat scratch, and HIV.

Craniofacial pain can also be treated by the above described cranialadministration method. The following non-limiting examples can betreated by the method of the invention. Anesthesia dolorosa, centralpost-stroke pain, facial pain attributed to multiple sclerosis,persistent idiopathic facial pain, burning mouth syndrome,glossopharyngeal neuralgia, nervus intermedius neuralgia, occipitalneuralgia, postherpetic neuralgia, raeder paratrigeminal syndrome,superior laryngeal neuralgia, trigeminal neuralgia, cluster-ticsyndrome, cancer pain, dental pain, giant cell arteritis, posttraumaticand postoperative pain, primary headache, and temporomandibular jointsyndrome,

The cranial delivery method can also be used for treating ophthalmicdiseases, including but not limited to glaucoma, allergicconjunctivitis, ocular rosacea, retinal vasculitis, bullous pemphigoid,mucous membrane pemphigoid, Sjogren's syndrome, episcleritis, scleritis,uveitis, optic neuritis, ischemic optic neuropathy, pain, dry eye,macular degeneration, diabetic retinopathy, herpes simplex keratitis, orendophthalmitis.

Cranial delivery of progesterone is effective for treating eyediscomfort resulting from iatrogenic causes, including but not limitedto medication use (e.g., anti-histamines, glaucoma medication,immunosuppressants such as cyclosporine), and surgical procedures (e.g.,laser eye surgery, cataract operations, and corneal transplants).

Progesterone applied cranially is effective for treating ocular tissuedamage, such as epithelial defects, ocular allergy such as those causedby seasonal, perennial, animal, insect, or other environmentalallergens, and ocular redness that can be conjunctival, caused by eyestrain or irritation.

As mentioned above, cranial delivery can allow a drug to reach an areaof the body that cannot be reached by other means of administration,such as behind the eye. Thus, within the scope of this invention iscombination therapy with at least two drugs, one administered craniallyand one administered directly to the front of the eye. For example,progesterone, ganciclovir, or both can be administered craniallyconcomitant with an antibiotic administered to the front of the eye fortreating ophthalmic diseases.

Acquired neurodegenerative diseases can also be treated by the methoddescribed supra. For example, the method can be used for treatingamyotrophic lateral sclerosis (ALS), progressive supranuclear palsy(PSP), Parkinson's disease, multiple system atrophy, corticobasaldegeneration (CBD), Alzheimer's disease, dementia with Lewy bodies,frontotemporal dementia, and poststroke dementia.

Also treatable by cranial drug delivery are acquired immune orinflammatory disorders, such as peripheral neuropathy associated withinfection by Borellia burgdorferi (Lyme disease), Chagas disease,leprosy (Hansen's disease), rabies virus, inflammatory neuropathies,Guillain-Bane syndrome (GBS), chronic inflammatory, demyelinatingpolyneuropathy (CIDP), Sjogren's syndrome, systemic lupus erythematosus,and multiple sclerosis.

Certain embodiments are set out below.

Disclosed is the use of a topical progesterone composition for treatingcontact lens discomfort, eye discomfort resulting from iatrogeniccauses, ocular allergy, ocular tissue damage, ocular redness,inflammatory conditions of the eye, blepharitis, meibomian cyst,uveitis, punctate keratitis, retinitis, dyslexia, pain, neuralgia,blepharospasm, and facial palsy, wherein the composition is administeredto an area of the face not including the palpebral part of the eye. Thearea of the face not including the palpebral part of the eye can be theforehead, the temple region, the upper cheek, or the bridge of the nose.

Also disclosed is the use of a topical progesterone composition forstimulating eyelash and eyebrow growth, wherein the composition isadministered to an area of the face not including the palpebral part ofthe eye. The area of the face not including the palpebral part of theeye can be the forehead, the temple region, the upper cheek, or thebridge of the nose.

Further disclosed is the use of a topical cannabinoid composition forreducing behavioral and psychological symptoms associated with dementiaand for treating surgically-induced cognitive and speech defects,cerebral palsy, anorexia, nausea, and oropharyngeal dysphagia, whereinthe composition is administered to an area of the face not including thepalpebral part of the eye. The area of the face not including thepalpebral part of the eye can be the forehead, the temple region, theupper cheek, or the bridge of the nose. A dose of cannabinoid from 0.1mg to 20 mg can be administered. The cannabinoid can be dronabinol. Theoropharyngeal dysphagia can be caused by an injury, an infection, ametabolic condition, an autoimmune condition, a neurological condition,a structural defect, or a medical treatment.

Also provided is the use of a topical anxiolytic composition forrelieving anxiety, wherein the composition is administered to an area ofthe face not including the palpebral part of the eye.

Further provided is the use of an antimicrobial agent for treating adisease or condition mediated by a neurotropic microbe, wherein thecomposition is administered to an area of the face not including thepalpebral part of the eye. The area of the face not including thepalpebral part of the eye can be the forehead, the temple region, theupper cheek, or the bridge of the nose. The neurotropic microbe can be aneurotropic virus and the antimicrobial agent can be ganciclovir,acyclovir, valganciclovir, ribavirin, famciclovir, oseltamavir,docosanol, penciclovir, cidofovir, rimantadine, zanamivir, or foscarnet.The condition mediated by a neurotropic microbe can be a surface oculardisease. The neurotropic microbe can be Varicella zoster or Herpessimplex. The disease mediated by a neurotropic microbe can be herpetickeratitis.

Additionally provided is a method for treating an ophthalmic disease orcondition, the method comprising: identifying a subject having thedisease or condition, and administering topically a topical progesteronecomposition to an area of the face of the subject not including thepalpebral part of the eye, wherein the ophthalmic disease or conditionis selected from the group consisting of contact lens discomfort, ocularallergy, ocular tissue damage, ocular redness, allergic conjunctivitis,corneal damage, eye discomfort resulting from eye surgery or ocularmedication, blepharitis, meibomian cyst, uveitis, punctate keratitis,retinitis, vision problems associated with dyslexia, corneal lesions andthinning resulting from herpetic keratitis, shortened and sparseeyelashes and eyebrows, glaucoma, ocular rosacea, retinal vasculitis,ocular rosacea, bullous pemphigoid, mucous membrane pemphigoid,Sjogren's syndrome, episcleritis, scleritis, optic neuritis, ischemicoptic neuropathy, ocular pain, macular degeneration, diabeticretinopathy, herpes simplex keratitis, and endophthalmitis.

Also disclosed is the use of progesterone for the manufacture of atopical medicament for administering topically to an area of the face ofa subject not including the palpebral part of the eye for treating anophthalmic disease or condition selected from the group consisting ofcontact lens discomfort, ocular allergy, ocular tissue damage, ocularredness, allergic conjunctivitis, corneal damage, eye discomfortresulting from eye surgery or ocular medication, blepharitis, meibomiancyst, uveitis, punctate keratitis, retinitis, vision problems associatedwith dyslexia, corneal lesions and thinning resulting from herpetickeratitis, shortened and sparse eyelashes and eyebrows, glaucoma, ocularrosacea, retinal vasculitis, ocular rosacea, bullous pemphigoid, mucousmembrane pemphigoid, Sjogren's syndrome, episcleritis, scleritis, opticneuritis, ischemic optic neuropathy, ocular pain, macular degeneration,diabetic retinopathy, herpes simplex keratitis, and endophthalmitis.

Further provided is a method for treating oropharyngeal dysphagia, themethod comprising: identifying a subject having oropharyngeal dysphagia,and administering topically a topical cannabinoid composition to an areaof the face the subject not including the palpebral part of the eye. Theoropharyngeal dysphagia is associated with side effects of medication,neuroleptics, postsurgical muscular or neurogenic causes, radiation,diphtheria, botulism, Lyme disease, syphilis, polio, postpolio syndrome,herpes, cytolomegalovirus, candida, amyloidosis, Cushing's syndrome,thyrotoxicosis, Wilson's disease, overlap syndrome, dermatomyositis,myasthenia gravis, myotonic dystrophy, oculopharyngeal dystrophy,polymyositis, sarcoidosis, paraneoplastic syndrome, brainstem tumors,head trauma, stroke, cerebral palsy, Guillain-Barre syndrome,Huntington's disease, multiple sclerosis, tardive dyskinesia, metabolicencephalopathies, amyotrophic lateral sclerosis, Parkinson's disease,achalasia, or dementia.

Additionally provided is the use of a cannabinoid for the manufacture ofa topical medicament for administering topically to an area of the faceof a subject not including the palpebral part of the eye for treatingoropharyngeal dysphagia.

Cranial Delivery of Psychoactive Compounds

Topical administration to the forehead is a novel and convenient way todeliver pharmaceutical compounds that act on the central nervous system.These include, e.g., stimulants, antipsychotics, anxiolytics,benzodiazepines, antidepressants, anti-narcoleptics, muscle relaxants,anticonvulsants, analgesics. Other pharmaceuticals that can be deliveredby this method include, but are not limited to, those pharmaceuticalsfor treating for bipolar disorder, insomnia, dementia, fibromyalgia,multiple sclerosis, neuromuscular disorders, Parkinson's disease,attention deficit hyperactivity disorder (ADHD), narcolepsy, Alzheimer'sdisease, seizure disorders. A more complete list is shown in Table 1below.

TABLE 1 Neuroactive drugs that can be administered topically to theforehead grouped by drug type or medical conditions. ADHD FluphenazineDextroamphetamine Haloperidol Amphetamine Perphenazine MethylphenidateTrifluoperazine Dexmethylphenidate Loxapine Atomoxetine PimozideGuanfacine Thioridazine Lisdexamfetamine Thiothixene ClonidineAntipsychotics, 2nd Generation Methamphetamine AripiprazoleAntipsychotics, 1st Generation Clozapine Chlorpromazine OlanzapineQuetiapine Risperidone Clomipramine Paliperidone Desipramine ZiprasidoneDoxepin Iloperidone Imipramine Asenapine Nortriptyline AnxiolyticsProtriptyline Buspirone Trimipramine Hydroxyzine Meprobamate OtherAntidepressants Benzodiazepines, Short Acting Bupropion AlprazolamMirtazapine Midazolam Trazodone Oxazepam Nefazodone Benzodiazepines,Mid-Acting Vilazodone Lorazepam Narcolepsy Benzodiazepines, Long-ActingModafinil Chlordiazepoxide Armodafinil Diazepam Caffeine ClorazepateOther Bipolar Disorder Lurasidone Aripiprazole Maprotiline CarbamazepineNeurological Disorders Lithium Alzeheimer's disease/Dementias OlanzapineDonepezil Insomnia Memantine Hydroxyzine Rivastigmine LorazepamGalantamine Doxepin Fibromyalgia Monoamine Oxidase InhibitorsMilnacipran Phenelzine Pregabalin Selegiline FosphenytoinTranylcypromine Multiple Sclerosis Serotonin-norepinephrine reuptakeGlatiramer inhibitors Neuromuscular Disorders Duloxetine PyridostigmineVenlafaxine Hydroxide Desvenlafaxine Neostigmine Selective SerotoninReuptake Riluzole Inhibitors Parkinson's Disease CitalopramCarbamazepine Escitalopram Carbidopa Fluoxetine Levodopa ParoxetineApomorphine Sertraline Bromocriptine Fluvoxamine Pramipexole VilazodoneRotigotine Tricyclic Antidepressants Ropinirole Amitriptyline SelegilineSeizure Disorders Fentanyl Rufinamide Hydrocodone DivalproexHydromorphone Phenytoin Levorphanol Levetiracetam Meperidine LamotrigineMethadone Vigabatrin Morphine Ethosuximide Nalbuphine PrimidoneOxycodone Valproic Acid Oxymorphone Topiramate Pentazocine LacosamideTapentadol Zonisamide Tramadol Gabapentin Opium Felbamate PropoxypheneTiagabine Other Analgesics Oxcarbazepine Rizatriptan Other EletriptanTetrabenazine Zolmitriptan Gabapentin Enacarbil Butalbital EntacaponeDiphenhydramine Rasagiline Frovatriptan Fampridine Almotriptan BotulinumA Toxin Dihydroergotamine Benztropine Naratriptan Amantadine NaloxoneDextromethorphan Naltrexone Quinidine Salsalate Tolcapone DiflunisalBotulism Antitoxin B Ergotamine Trihexyphenidyl IsomethepteneMethsuximide Phenyltoloxamine Ethotoin Clonidine Capsaicin MentholProcyclidine Camphor Physostigmine Pamabrom Dexpanthenol MeprobamateAmbenonium Methapyrilene Guanidine Phenobarbital BethanecholPhenylephrine Promethazine Analgesics Sumatriptan Opioids MuscleRelaxants Buprenorphine Cyclobenzaprine Butorphanol Carisoprodol CodeineDantrolene Codeine Baclofen Dihydrocodeine Chlorzoxazone ChlorzoxazoneMethyltestosterone Orphenadrine Mometasone Methocarbamol DiflorasoneTizanidine Lanreotide Zoledronic Acid Fludrocortisone RaloxifeneOxandrolone Teriparatide Flurandrenolide Metaxalone Tesamorelin AcetateCisatracurium Halobetasol Colecalciferol Mecasermin RocuroniumLevonorgestrel Quinine Hydroxyprogesterone Vecuronium ClocortoloneSuccinylcholine Drospirenone Pamidronic Acid Halcinonide AtracuriumVasopressin Caffeine Oxytocin Etidronic Acid MethylergonovineErgocalciferol Danazol Pancuronium Clomiphene Tiludronate AlclometasonePhenyltoloxamine Cetrorelix Hormones Norgestimate Testosterone NafarelinSomatropin Oxymetholone Estrogenic Sub, Conjugated Estropipate EstradiolTriamcinolone Hexacetonide Betamethasone Amcinonide ClobetasolFluoxymesterone Methylprednisolone Cortisone HydrocortisoneTriamcinolone Acetonide Antiviral Agents with Efficacy for ProgesteroneHead and Neck and CNS Medroxyprogesterone Valacyclovir NorethindroneAcyclovir Calcipotriene Valganciclovir Desmopressin RibavirinDesoximetasone Famciclovir Desonide Oseltamavir Fluocinonide DocosanolDinoprostone Penciclovir Dexamethasone Ganciclovir PrednisoloneCidofovir Fluticasone Rimantadine Ethinylestradiol ZanamivirCorticotrophin Foscarnet Prednisone Anti-Infectives With Efficacy ForFluocinolone Acetonide Head And Neck And CNS Minocycline BetaxololDoxycycline Levobunolol Vancomycin Carteolol Azithromycin Alpha-1Agonist and Partial Alpha-2 Clindamycin Agonist Meropenem OxymetazolineCeftriaxone Steroids Clarithromycin Dexamethasone Cefepime LoteprednolEtabonate Erythromycin Prednisolone Cefpodoxime Hydrocortisone ProxetilFluorometholone Metronidazole Difluprednate Amikacin RimeloxoneTetracycline Fluocinolone Acetonide Antifungals With Efficacy For HeadTriamcinolone And Neck And CNS Acetonide Voriconazole Carbonic AnhydraseInhibitors Micafungin Dorzolamide Amphotericin B BrinzolamideItraconazole Acetazolamide Ketoconazole Caspofungin NSAIDs PosaconazoleBromfenac Fluconazole Nepafenac Flucytosine Flurbiprofen ImmunologicAgents Ketorolac Tacrolimus Diclofenac Lenalidomide Macular DegenerationSirolimus Verteporfin Thalidomide Anesthetics Cyclosporine ProparacaineEverolimus Tetracaine Ophthalmic Preparations Lidocaine ProstaglandinsAnticholinergics Travoprost Tropicamide Bimatoprost HomatropineLatanoprost Glaucoma Agents Calcineurin Inhibitor Carbachol CyclosporineEcothiopate Methazolamide Alpha-Adrenergic Agonists Mast CellStabilizers Brimonidine Nedocromil Apraclonidine LodoxamidePhenylephrine Cromolyn Beta Blockers Pemirolast Timolol PotassiumMetipranolol Other Scopolamine Ingredient Pilocarpine Sedatives andHypnotics Acetylcholine Zolpidem Hydroxide Eszopiclone Anti-VEGFTemazepam Pegaptanib Ramelteon Sympathomimetic Drug PentobarbitalHydroxyamphetamine Phenobarbital Anti-infectives Other Than AntiviralDoxepin Moxifloxacin Zaleplon Tobramycin Diphenhydramine GatifloxacinDoxylamine Polymyxin B Triazolam Erythromycin MethylphenobarbitalAzithromycin Secobarbital Neomycin Melatonin Bacitracin EstazolamGentamicin Chloral Hydrate Ganciclovir Butabarbital Ofloxacin FlurazepamBesifloxacin Amobarbital Trimethoprim Methapyrilene SulfacetamideScopolamine N-Oxide Ciprofloxacin Dimenhydrinate Trifluridine QuazepamLevofloxacin Scopolamine Gramicidin Cardiac Agents Natamycin EpinephrineOxytetracycline Ranolazine Antihistamines Dronedarone BepotastineNitroglycerin Azelastine Propafenone Pheniramine Isosorbide-5-Epinastine Mononitrate Alcaftadine Digoxin Ketotifen NesiritideEmedastine Amiodarone Olopatadine Midodrine Antazoline IsosorbideDinitrate Dipivefrine Flecainide Sotalol Sexual Function DisorderMilrinone Sildenafil Indomethacin Tadalafil Hydralazine VardenafilDofetilide Alprostadil Disopyramide Benzocaine Dobutamine NonPharmaceutical Dopamine Isoproterenol Varenicline Procainamide NicotineQuinidine Bupropion Ibutilide Nikethamide Mexiletine Cough/Cold/FluPreparations Amyl Nitrite Dextromethorphan Ubiquinones ChlorpheniramineAmrinone Guaifenesin Moricizine Phenylephrine AntinauseantPseudoephedrine Palonosetron Doxylamine Fosaprepitant BrompheniramineDronabinol Homatropine Ondansetron Promethazine Aprepitant BenzonatateScopolamine Carbetapentane Promethazine Pyrilamine MeclizineDiphenhydramine Granisetron Chlophedianol ProchlorperazineDexchlorpheniramine Trimethobenzamide Ephedrine DimenhydrinateGuaiacolsulfonate Dolasetron Chlorcyclizine Nabilone DexbrompheniramineCyclizine Clofedanol Noscapine Thyroid Therapy Pheniramine LevothyroxineTriprolidine Liothyronine Bromodiphenhydramine Methimazole CarbinoxaminePropylthiouracil Methscopolamine Smoking Deterrents Phenindamine

Without further elaboration, it is believed that one skilled in the artcan, based on the disclosure herein, utilize the present disclosure toits fullest extent. The following specific examples are, therefore, tobe construed as merely descriptive, and not limitative of the remainderof the disclosure in any way whatsoever. All publications and patentdocuments cited herein are incorporated by reference.

Example 1 Treatment of Drug-Induced Anorexia and Oropharyngeal Dysphagia

A patient had been on dexamethasone therapy for 20 months followingsurgery, radiation, and chemotherapy. After tapering the dose ofdexamethasone from 16 mg per day to 1.5 mg per day, the patient wasunable to swallow and reported a loss of appetite. Dronabinol wasadministered to the patient's forehead once per day at 2.5 mg per dose.Improvement in swallowing and appetite were noted within 24 hours of thefirst administration. The patient reported a healthy appetite and noproblems swallowing after four weeks of topically applied dronabinol.

After missing one day of dronabinol therapy, the patient reported adecrease in appetite and difficulty swallowing liquids. Restoration ofcranial dronabinol therapy resulted in a normal appetite and swallowingafter one day. After three weeks of continued dronabinol therapy,application was again stopped for 24 hours, resulting in the same lossof appetite and difficulty swallowing. The patient reported a completereversal of symptoms within about two hours after a single dose ofdronabinol to his forehead.

The effect of oral administration of dronabinol was tested after anothertwo weeks as an alternative to the topical route of administrationdescribed above. Within one day after starting oral administration of2.5 mg dronabinol, the patient had difficulty swallowing and chewing.Patient was rescued again by single dose applied cranially and iscurrently eating normally and chewing and swallowing. Typical mealsinclude steak, meatball sandwich and fruit drinks.

Continued treatment after one year including multiple challenge stopsand restarts of cranial drug dosing confirms that daily dosing isnecessary for continued effectiveness. No increase in dose has beenrequired. The patient had also ceased dexamethasone dosing very earlyon.

Example 2 Treatment of Surgically Induced Cognitive Deficits

The patient described in Example 1 suffered from a co-morbid conditionof cognitive impairment due to surgery to remove a frontal lobeglioblastoma multiforma. The cognitive impairment continued for twoyears following the surgery at which time treatment with craniallydelivered dronabinol was begun. The patient's physicians have noted,since cranially delivered dronabinol therapy was initiated, a dramaticimprovement in cognitive function, as well as a noticeable decrease inscar tissue around the area of surgery as detected by imaging.

Example 3 Treatment of Trigeminal Neuralgia and Facial Palsy

A subject presented with left-side trigeminal neuralgia and left sidefacial droop of 10 years duration.

Therapy was initiated by topically applying progesterone (1% by weight)equivalent to 1 mg four times daily to the patient's forehead. This wasfollowed by application of 0.15 g ganciclovir (as a 0.15% by weightformulation) up to five times daily.

The treatment resulted in relaxation of facial muscles that had beencontracted for 10 years after a herpes virus infection.

Example 4 Treatment of Herpetic Keratitis

A 67 year old male suffered a first onset of active corneal Herpeszoster at age 56. He presented with classic Herpes Zoster symptomsincluding, left hemisphere unilateral skin lesions on forehead, bridgeof nose area and down the nose not including the tip; left corneadendrites, keratitis and edema; loss of functional vision, elevatedintraocular pressure as high as 42 mm Hg, conjunctiva! irritation andredness and anesthetic cornea. There were also general body flusymptoms. The individual had a history of childhood chickenpox andmononucleosis.

The patient was initially treated with ophthalmic prednisolone acetate1% up to 5 times daily, ophthalmic antibiotics, non-prescriptionophthalmic wetting agents, and lubrication with gels administered to theeye. Additional drug therapies included systemic oral valcyclovir ashigh as 2 g per day and medications to reduce intraocular pressure.

The treatment regimen did not result in any return of functional vision.Despite the therapy, symptom flare-up was as frequent as 2 weeks to 1month over the past 10 years. Although intraocular pressure returned towithin the normal range, cataracts formed as a result of long term useof corticosteroids.

The cornea began to demonstrate surface thinning with a loss ofepithelial cells. The cornea surface contour became increasinglydistorted with prominent ridges. There was incursion of capillariesacross the conjunctiva into the cornea, both superficially and deep.Deposition of phospholipids through a leaching process occluded thecornea with grey color deposits on about 50% of its surface.

An ophthalmological exam revealed edema and large areas of phospholipiddeposits. Corneal thinning had progressed to near perforation levelswhich required preparation for corneal patch surgery.

At this point, 1% topical progesterone (approximately 1 mg ofprogesterone) was first administered as a method to keep the cornea fromperforating and the tear film intact. The drug was applied to theforehead 4 times daily together with topical antibiotics andcorticosteroids. Further corneal deterioration was halted and graduallyall other medications other than the topical progesterone were stopped.During a one year period of treatment 2 or 3 times a day with 1 mgprogesterone to the forehead and no other drugs, the cornea remainedunperforated.

After stabilizing the cornea, antiviral treatment was begun withganciclovir gel (0.15%; 0.15 mg of drug) applied five times. daily tothe forehead together with once daily progesterone (1%; 1 mg of drug)and a nightly drop of ophthalmic antibiotic. Intraocular pressuremeasured at the onset of ganciclovir treatment was 18 mm Hg.

The patient reported a decrease in eye strain as a result of animprovement in tear film. After 1 week of treatment with the two drugs,there was less inflammation and a slight improvement in visual acuity inparticular in high contrast fields of view to close on object. Over thenext two weeks, inflammation was further reduced and visual acuityincreased somewhat when the head was tilted back. During the first fullmonth of treatment, the affected eye generally felt comfortable. Therewas a lack of inflammation, and some vision returned to the threshold offunctionality. Intraocular pressure remained normal in the range of 16mm Hg.

An examination revealed that the particular area was in fact clearer butnot further thinning. There was modest improvement in reading the eyechart, and corneal staining due to defects was minimized. Intraocularpressure remained normal in both eyes at about 16 mm Hg during thisperiod. The phospholipid deposits further reduced in density and beganto give the appearance of lesser areas of concentrations. Nearlyfunctional vision could be achieved by positioning the head back andviewing through the central cornea. The residual clear area of thecornea became more so and less inflamed. Through the end of the secondmonth, improvement to the cornea accelerated. The pupil was now clearlyvisible and more light was entering the eye. By the third month, thelipid sectors were noticeably reduced and some functional vision wasattained.

The patient was examined regularly by an ophthalmologist, and afterthree and one half months of treatment. The intraocular pressure wasnormal at 12 mm Hg. The affected eye was considered stable andnormalizing. The reduction of the intraocular pressure demonstratedreduction in inflammation. Intraocular pressure has remained in the samerange for more than one year.

Example 5 Treatment of Dyslexia and Impaired Executive Brain FunctionExacerbated by Traumatic Brain Injury

A 52 year-old male patient had been diagnosed in childhood withdyslexia. Symptoms included unstable binocular fixation while reading,the inability without compensating to find the end of one line andbeginning of the next, and double overlapping perception of lines ofprint. He was also unable to read aloud in a fluid manner.

The individual applied a topical gel containing 4% by weightprogesterone (4 mg of drug) to the forehead area. The patient reportedthat within 60 seconds his eyes relaxed into alignment, the effectlasting for hours.

The application was repeated twice over the next few days and thepatient tested himself by reading text. The patient reported slightlybetter and easier reading and line tracking. The treatment benefitlasted for about four hours.

Regular treatment was continued for 10 weeks with the 4% progesteronegel applied to the forehead twice daily. The patient reported that inliving with dyslexia for 52 years, he had never experienced as muchstress relief in his visual system after the treatment. He was able totrack from one end of a line of text to the beginning of the next linewithout using a ruler for assistance. He can read aloud with lesschoppiness.

After 8 weeks of treatment, the individual was asked to read aloud acomplex paragraph of 8 sentences from his computer screen. Hisarticulation was accurate and fluid with only one word lapse.

Treatment was interrupted after 10 weeks to determine the duration ofbenefit. Ten days later, the individual reported continued benefit withonly slight degradation.

Seven years prior to initiation of progesterone topical treatment, thepatient had suffered traumatic brain injury (TBI) in an auto accident.He reported exacerbation of his vision problems as a result of theaccident.

After treatment, in addition to improved reading ability discussedabove, he experienced improved executive function which is commonlydamaged by TBI. He reported a much lower level of stress. After thecrash he suffered from post traumatic stress disorder triggered by loudsounds. The patient could not even listen to music because it wouldinduce nausea. Two months after initiation of the progesteronetreatment, he regained a good deal of social conformability, improvedhis ability to organize thoughts, eliminated his disjointed thinking,and gained the ability to write coherently. He also reported the abilityto do simple math in his head, having been unable to perform that taskfor the 7 plus years prior to the treatment.

A 51 year old female who had been diagnosed with severe reading problemsin third grade was later recognized as having dyslexia. Her readingproblems became exacerbated by an automobile accident in 1980 at 18years of age, following six months of coma. In general reading was achore. However she made a concerted effort to learn to read, startingwith children's books, and is now able to read regular print. Readingissues were exemplified by the need to place a ruler below each line sothat she can follow the line and find the next line, and seeing lettersbackwards. She is not able to read small print at all. About 4 years agoher vision became worse. She was prescribed glasses that she uses duringperiods when vision is worse than usual, whether near, intermediate, orfar in distance.

A 1% progesterone topical composition was applied to her forehead. About5 minutes later, she could “feel a clearing in her head”. She was ableto read without using a ruler or glasses. Her distance vision alsoimproved. When driving that night, she was no longer bothered by theheadlight glare from oncoming cars. The effect lasted from the time ofapplication, around 7:30 pm to bedtime at around 11 pm. Reapplicationnext morning restored vision improvements.

Example 6 Treatment of Symptoms Associated with Alzheimer's Disease

An 84 year old female diagnosed with late stage Alzheimer disease fiveyears ago suffers from episodes of extreme agitation, aggressivebehavior, and nocturnal restlessness and disorientation that isdifficult for her caregiver to manage. Approximately 2 mg dronabinol wasdelivered cranially to her forehead.

An improvement in her symptoms were observable within two hours ofdronabinol application, including less frequent nocturnal disturbances.Continued daily dosing provided additional significantly noticeableimprovement in her symptoms.

Example 7 Treatment of Ocular Discomfort Associated with Dry Eye andContact Lenses

Twenty-seven patients diagnosed with ocular discomfort resulting fromdry eye were treated with topical progesterone (0.5%4% by weight,corresponding to approximately 1-4 mg progesterone per application)applied to the forehead either once or twice per day.

Improvement was seen in all cases. Most patients were able todiscontinue previous therapy including eye drops and artificial tears. Asummary of clinical results is shown below in Table 2.

TABLE 2 Treatment of dry eye with topical progesterone applied craniallyMcMonnies' Progesterone Formulation Subject Gender Score* Used Results 1F 27 0.5-1% on the forehead, Diagnosed with Sjogren's syndrome. oncedaily. Eyes moist and tearing minutes after application. Stopped allauxiliary eye drops. After prolonged use, no longer requires. 2 F 17 1%progesterone BID Eyes tear minutes after application above the brows. 3F 12 1% progesterone BID Eyes tear minutes after application above thebrows. Could stop eye drop use. 4 F  9 1% progesterone No noticeableimmediate effect but moisture felt after 10 minutes; after weeks of use,no redness or acuity problem after extended computer use as encounteredpreviously. 5 M not 1% progesterone 74 year old male had problem for 3determined decades of hypertearing including mucus secretion,photosensitivity, and itching. Could not drive at night due to glare.After 3 months of using product twice a day, all problems wereeliminated including itching. Could drive at night again. 6 F 14 1%progesterone Previous: Bloodshot eyes and reduced acuity at end of day,discharge in the morning. Started using product before bedtime -prevented discharge in the morning and acuity and redness at end of day.7 F 28 1% progesterone BID Prev. dry eyes with mucus discharge. Firstday after use, discharge decreased and later stopped. Continued to useproduct for 2 months until ran out of product - yellow dischargereturned when use ceased. 8 F 12 1% progesterone Increased tearproduction, acuity, prevented mucus discharge and redness. 9 F 14 1%progesterone ON Suffers from severe dry eye at night that wakes her upwithout intervention. Had been using petrolatum ointment. Has beenapplying on forehead over eyebrows. Equally effective. Uses nightly oncea day only usually. 10 F 18 1% progesterone BID Patient had severe eyeproblems that affected her vision. Recently diagnosed with Fuchdystrophy, a genetic disorder, and about a week prior had a partialcorneal transplant. Post surgery eyes were uncomfortable. Reportedrelief upon progesterone therapy when used 2-3 times a day. 11 F 22 1%progesterone BID Patient had severe dry eyes. Previous regimen: For atleast 2 years, Restasis ™ morning and evening. Eye ointment at bedtime.“Oily” eyedrops between 4-5 am each morning. Patient applied 1%progesterone. For first 2 weeks she reported marginal results, but onweek 3 she felt that the 1% progesterone adequately replaced allprevious treatments. 12 F 17 1% progesterone Reported “marked decrease”in “gritty” feeling. 13 M 11 1% progesterone Reported product works,prevents “gummy” exudate and eye fatigue. 14 F not 1% progesterone Airstewardess uses twice a day on determined flights over 6-7 hours forcomfort and preventing red eyes. 15 F 21 1% progesterone Tear productionin seconds. Redness disappeared. 16 F 22 1% progesterone BID Extremehyper-tearing began easing following the first dose, and there was lessirritation and dryness next morning. Hyper-tearing completely stopped bythe third day. Antihistamine tablet use caused a slight temporaryreversal 3 weeks later. 17 F not 1% progesterone TID Stopped usinglubricating drops. determined Redness, itching and scaly eyelidsdisappeared. Previously multiple eye surgeries, one to remove calciumdeposit. Was also taking glaucoma medications. 18 F not 1% progesteroneBegan using 2-3 times/day. Eyelids no determined longer sticky after 2days of use. Chronic dry mouth gone after a few minutes. TBUT increasedfrom 2 to 8. Long term improvement, only occasional “sticky eyelids”. 19F not 0.75% or 1% progesterone Eyes felt “less dry in the morning”.determined BID Previous ocular grittiness and burning. Past Lasik;concurrent thyroid disease and antihistamine tablets. 20 F not 0.75% or1% progesterone Immediate production of tears, and eyes determined BIDnot so dry in the morning. Previously dryness, grittiness, eyeirritation upon waking, artificial tear usual, HRT, thyroid disease. 21F not 0.75% or 1% progesterone More comfort, less red. Previouslydetermined BID chronic dryness, burning, irritation with only slightimprovement with artificial tears. 22 F not 0.75% or 1% progesteroneMore comfortable, less photosensitive, determined BID and less redwithin two hours. 23 F not 0.75% or 1% progesterone Improved eye comfortand eye moisture determined BID within half hour. Fewer meibomian cystsalong lid margin. 24 F not 0.75% or 1% progesterone Increased visualacuity in twenty determined BID minutes, less glare, halos andphotosensitivity. Previous glare and decreased vision at night, problemsdriving. Punctal plugs relieved symptoms. 25 F not 0.75% or 1%progesterone More comfortable and increased tear determined BIDproduction, less red. Previous complaints of “sandy gritty sensation”.26 F not 0.75% or 1% progesterone More comfortable and moisture withindetermined BID half hour. 27 F not 0.75% or 1% progesterone Improvedquality of tears, moisture and determined BID comfort. *A score of over20 is indicative of dry eye, while a total score of between 10 and 20 issuggestive of borderline dry eye disease.

Ten individuals reporting ocular discomfort resulting from wearingcontact lenses were treated with topical progesterone (0.25%-1% byweight, corresponding to approximately 1-4 mg progesterone perapplication) applied to the forehead either once or twice per day. Allindividuals reported elimination of discomfort, irritation, redness,grittiness, and burning. Additionally, individuals were able to weartheir contact lenses for a longer period of time as compared to beforetreatment. The individuals also reported that it was easier to insertand remove their lenses. An improvement in visual acuity was alsoreported. A summary of clinical results is shown below in Table 3.

TABLE 3 Treatment of contact lense discomfort with topical progesteroneapplied cranially Progesterone Formulation Subject Gender McMonnies'Score* Used Results 1 F 13 1% progesterone Eyes tear minutes afterapplication to either over the eyes or above the brows. Helped withredness. Air conditioning very irritating. Reported that 1% progesteronewas effective. Reported product helped with seasonal and felineallergies. 2 F 14 1% progesterone Previous: Bloodshot eyes and reducedacuity at end of day, discharge in the morning. Started using productbefore bedtime - prevented discharge in the morning and acuity andredness at end of day. Contacts used for 1 week felt like new. 3 F 24 1%progesterone BID Product eliminated discomfort, irritation and burningdue to contact lens wear. 4 F not determined 1% progesterone Productworked well for eyes. Prolongs contact lens wearing time and comfort.Suffers wet macular degeneration, receiving Lucentis treatment. 5 F notdetermined 1% progesterone BID Diagnosed April 2011. Blurred vision,stickiness, irritation with contact lenses >6 hours. Difficult to removesoft lenses at end of day. Refresh 4 times a day provided relief fromstickiness only. Moisture in eyes within minutes of treatmentinitiation. Within days irritation and blurred vision improved. Whenstopped using, symptoms reappeared. Resumed with 0.25% each night as ofbeginning of December 2013. Able to wear soft lenses for up to 12hours/day without irritation, with ease of insertion and removal. 6 Mnot determined 0.5% progesterone Redness from contact lens wearimmediately resolved after application. 7 F not determined 0.75% or 1%progesterone Moisture and tear production BID increase within half hour.Improvements in ocular comfort, photosensitivity, redness andgrittiness. No longer difficulty in opening eyes in the morning. Canleave contact lenses in all day until bedtime, much longer than before.8 F not determined 0.75% or 1% progesterone Applied only over the lefteye, BID but both eyes improved within 3-4 minutes. Visual acuityimproved. Less discharge in the morning. Lenses “felt like new”. 9 F notdetermined 0.75% or 1% progesterone Had problems tolerating BID contactlenses. Eyes were moist within 20 minutes of application, and morecomfort within 40 minutes. Can wear contacts longer. 10 F not determined0.75% or 1% progesterone Increased contact lens BID tolerance andgeneral ocular comfort. *A score of over 20 is indicative of dry eye,while a total score of between 10 and 20 is suggestive of borderline dryeye disease.

Example 8 Treatment of Blepharospasm

A 58 year old female had a blink rate averaging 73 times per minute.Upon ophthalmic re-examination following fourteen days of 1%progesterone gel applied topically to the forehead, the blink rate haddecreased to 18 times per minute.

Example 9 Treatment of Drug-Induced Eye Irritation

A 68 year old male and a 68 year old female induced eye irritation byapplying three drops of 0.05% cyclosporine emulsion onto the forehead.Within five minutes the eyes became irritated and stinging, and theeyelids became heavy. There was no production of moisture. Thediscomfort intensified with time. Ten minutes later, drug residual wascleaned off from the forehead, and 1% progesterone was applied. Withintwo minutes, the irritation and stinging began to dissipate.

Example 10 Stimulation of Eyelash and Eyebrow Growth

A 67 year old post-menopausal female had lost all of her eyelashesfollowing chemotherapy and no spontaneous re-growth occurred in the nineyears since the treatment ceased. Cranial application of 1% progesteronegel (1 mg) was initiated once daily. After two weeks, her upper andlower lashes began growing and were noticeable. Her lashes fell outafter halting progesterone administration. Upon reapplication of atleast 1% progesterone daily, eyelash growth resumed. The appearance anddisappearance of eyelashes was uniform across her upper and lowereyelids.

A 45 year old female reported eye brow growth after applying 0.75% to 1%progesterone to the forehead for several days.

A 62 year old female reported eye lash and eye brow growth afterapplying 1% progesterone to the forehead for 3 weeks.

A 67 year old male applied 1% progesterone (1 mg) daily to his foreheadand experienced significant growth to the upper and lower eyelashes as aunit. Following one year of intermittent application of progesterone gelonce or twice a week, his eyelash shafts were thicker and naturallycurled up and down away from the eyes. Since beginning progesteronetherapy, there has been minimal lash loss on any of his eyelids. Theouter limit for the growth of any particular lash has not been reachedand lashes continue to lengthen as a unit. Lashes filled in rows on lidmargins where none were apparent and density has noticeably increased.Application of progesterone also resulted in eyebrow growth.

A 74 year old male had lost his eyebrows as a result of Hashimoto'sthyroiditis. Application of 1% progesterone gel daily resulted ineyebrow growth within the first two weeks of use.

Example 11 Treatment of Dry Eye in Domestic Animals

A puggle presented with mucus discharge from the eyes. Application ofprogesterone to the dog's forehead resulted in improved symptoms within24 hours. After using the daily topical forehead treatment for 4 days,the problem no longer recurred. The owner reported that the dog has thisproblem spring and fall, which indicates it is allergic seasonalrhinitis. The reported use took place in the fall.

A bulldog diagnosed with Sjogren's syndrome had mucus discharge from theeyes. The dog was being treated with tacrolimus directly in the eyewithout completely stopping the discharge. Topical application ofprogesterone was effective within 24 hours, resulting in a cessation ofmucus discharge.

Example 12 Treatment of Ocular Discomfort and Promotion of Ocular Health

A 68 year old male and a male between 25 and 45 years old applied asolution containing vitamin A, 1 mg xeaxanthin and 5 mg lutein on theforehead. Ocular comfort as exemplified by lubrication, less lidfriction, and less blinking was experienced within fifteen minutes.

Example 13 Treatment of Ocular Discomfort and Redness in Post-SurgicalPatients, and Patients on Glaucoma Medication

A female >80 years of age had four eye surgeries and was being treatedwith two glaucoma eye drops (dozolamide-timolol combination andtravaprost) together with a lubricating eye gel twice a day. Within onemonth of application to the forehead of 1% progesterone three timesdaily, subject was able to stop using the lubricating drops. Rednessalso disappeared.

A female >70 years of age had multiple surgeries and was diagnosed withFuch's corneal dystrophy and narrow angle glaucoma. Prior to the latestsurgery, when she was almost legally blind, she started applying to herforehead 1% progesterone 2-3 times a day, then reduced the applicationfrequency to once a day. Product helped to ease irritation, lid stickingand redness, some of which was associated with the surgery, glaucomadrops, and steroid drops.

Example 14 Treatment of Drug-Induced Anorexia

A 67 year old male who had taken 20 mg duloxetine HCl (CYMBALTA™) orallyfor short courses of 7 to 10 days once or twice a year over the courseof the last 10 years, experienced drug induced anorexia during the drugtherapy. This condition was quite pronounced after the second dailydose, with complete loss of appetite by the third dose. This reactionoccurred with every course.

The subject topically applied 2 mg of dronabinol to his forehead dailytogether with the oral CYMBALTA™. The topical dronabinol prevented theCYMBALTA™ induced loss of appetite over a 2 week course of treatment.

Example 15 Rapid Anti-Anxiety Treatment

A 67 year old male applied 1 mg of midazolam to his forehead on threeseparate occasions. Each application produced, within 5 minutes, a veryrapid response that developed into a state of mild sedation andanti-anxiety. These effects lasted for 4 to 6 hours after application ofthe drug.

Example 16 Treatment of Pain

A 67 year old female suffered a wrist fracture of the left distal radiusand ulnar styloid, with subsequent severe pain. Application ofapproximately 4 mg progesterone topically to the forehead resulted in asignificant decrease in pain within 15 minutes of application.

A 51 year old female was diagnosed 10 years ago with arthritis in herright wrist, with pain, weakness, and limited motion in the hand andwrist. Her ability to cut hair or open bottles, which requires torque,was greatly reduced. The condition has worsened since she was firstdiagnosed. The individual is being treated with regular steroidinjections. Five days after applying 1% progesterone to her forehead,she experienced significantly less wrist pain and increased mobility andstrength. She is able to twist open tightly closed containers.Additionally, bone snapping sounds and feelings are no longer present.

OTHER EMBODIMENTS

All of the features disclosed in this specification may be combined inany combination. Each feature disclosed in this specification may bereplaced by an alternative feature serving the same, equivalent, orsimilar purpose. Thus, unless expressly stated otherwise, each featuredisclosed is only an example of a generic series of equivalent orsimilar features.

From the above description, a person skilled in the art can easilyascertain the essential characteristics of the present disclosure, andwithout departing from the spirit and scope thereof, can make variouschanges and modifications of the present disclosure to adapt it tovarious usages and conditions. Thus, other embodiments are also withinthe claims.

1-35. (canceled)
 36. A method for treating an ophthalmic disease orcondition, the method comprising: identifying a subject having thedisease or condition, and administering topically a topical progesteronecomposition to an area of the face of the subject not including thepalpebral part of the eye, wherein the ophthalmic disease or conditionis selected from the group consisting of contact lens discomfort, eyediscomfort resulting from iatrogenic causes, vision problems associatedwith dyslexia, shortened and sparse eyelashes and eyebrows, and ocularpain. 37-38. (canceled)
 39. The method of claim 36, wherein the area ofthe face not including the palpebral part of the eye is the forehead,the temple region, the upper cheek, or the bridge of the nose.
 40. Themethod of claim 36, wherein a dose of progesterone from 0.01 mg to 20 mgis administered.
 41. The method of claim 39, wherein a dose ofprogesterone from 0.01 mg to 20 mg is administered.
 42. The method ofclaim 36, wherein the ophthalmic disease or condition is eye discomfortresulting from iatrogenic causes, the iatrogenic causes beinganti-histamines, glaucoma medications, immunosuppressants, laser eyesurgery, cataract operations, or corneal transplants.
 43. The method ofclaim 40, wherein the ophthalmic disease or condition is eye discomfortresulting from iatrogenic causes, the iatrogenic causes beinganti-histamines, glaucoma medications, immunosuppressants, laser eyesurgery, cataract operations, or corneal transplants.
 44. The method ofclaim 41, wherein the ophthalmic disease or condition is eye discomfortresulting from iatrogenic causes, the iatrogenic causes beinganti-histamines, glaucoma medications, immunosuppressants, laser eyesurgery, cataract operations, or corneal transplants.
 45. The method ofclaim 36, wherein the ophthalmic disease or condition is shortened andsparse eyelashes and eyebrows resulting from madarosis.
 46. The methodof claim 40, wherein the ophthalmic disease or condition is shortenedand sparse eyelashes and eyebrows resulting from madarosis.
 47. Themethod of claim 41, wherein the ophthalmic disease or condition isshortened and sparse eyelashes and eyebrows resulting from madarosis.48. A method for treating dyslexia, the method comprising: identifying asubject having dyslexia, and administering topically a topicalprogesterone composition to an area of the face of the subject notincluding the palpebral part of the eye.
 49. The method of claim 48,wherein the area of the face not including the palpebral part of the eyeis the forehead, the temple region, the upper cheek, or the bridge ofthe nose.
 50. The method of claim 48, wherein a dose of progesteronefrom 0.01 mg to 20 mg is administered.
 51. The method of claim 49,wherein a dose of progesterone from 0.01 mg to 20 mg is administered.52. A method for reducing behavioral and psychological symptomsassociated with dementia, the method comprising: identifying a subjecthaving behavioral or psychological symptoms associated with dementia,and administering topically a topical cannabinoid composition to an areaof the face of the subject not including the palpebral part of the eye.53. The method of claim 52, wherein the area of the face not includingthe palpebral part of the eye is the forehead, the temple region, theupper cheek, or the bridge of the nose.
 54. The method of claim 52,wherein a dose of cannabinoid from 0.01 mg to 20 mg is administered. 55.The method of claim 54, wherein the cannabinoid is dronabinol.
 56. Themethod of claim 53, wherein a dose of cannabinoid from 0.01 mg to 20 mgis administered.
 57. The method of claim 56, wherein the cannabinoid isdronabinol.